Antiseptics are substances intended for application to a living tissue of a mammal, which is an animal or human, to a mucous membrane in order to suppress the risk of infection, sepsis, or putrefaction.
Disinfectants are substances intended for application to non-living materials in order to destroy micro-organisms. Given the nature of the definition of antiseptics and disinfectants, some substances may simultaneously perform both antiseptic and disinfectant roles, according to their use. Depending on the concentration of the used substance with antiseptic or disinfectant activity, the given substances may have bacteriostatic or bactericidal effect. Substances with antiseptic or disinfectant activity may be prepared via chemical synthesis or isolated from plants, animals or their products (for example propolis or herbal products).
Antiseptics and disinfectants act using a non-specific mechanism against a wide spectrum of bacteria G+ and G−, fungi, viruses and yeasts.
Typical disinfectants and antiseptics include substances derived from quaternary ammonium salt (e.g., cetylpyridinium chloride), chlorhexidine and its salts (e.g., digluconate), phenolic compounds, sodium bicarbonate, terpenes, hypochlorite (calcium, sodium), peroxides, boric acid, and acetic acid. Widely used antiseptics include Povidone iodine, Benzalkonium, Aminotridecan, Benzydamine, Dichlorobenzyl alcohol/Amylmetacresol, hexetidine, and other substances with a proven disinfectant or antiseptic activity.
Natural antiseptics and disinfectants include for example extracts of Agrimonia eupatoria, Peppermint, Matricaria chamomilla, cloves, fennel, Salvia officinalis, Potentilla erecta; and other substances with a proven disinfectant or antiseptic activity.
One of the most typical antiseptics and disinfectants is chlorhexidine, a substance included in the WHO Model List of Essential Medicines, it has long been used for its excellent antibacterial activity. This may be, depending on the concentration, either bacteriostatic or bactericidal.
In gynaecology, chlorhexidine is used, due to its high effectiveness, to treat vaginal discharges and mixed infections (bacterial vaginosis and vulvovaginal candidiasis), (Pokorny M., New EU Magazine of Medicien 1-2/2013). In obstetrics, it is used for the treatment of umbilical cord of newborn babies. In veterinary medicine, chlorhexidine is used as a disinfectant of the skin, wounds and instruments.
In dentistry, it is used primarily for its ability to inhibit plaque formation and to suppress inflammation of the gums (gingivitis, parodontosis) in the oral cavity. Moreover, chlorhexidine is in dentistry used as the “gold standard” in testing of other substances, which are expected to inhibit plaque formation or suppress inflammation of the gums (gingivitis, parodontosis) (Jones C. G., Chlorhexidine: is it still a gold standard? Perio2000; 1997:15:55-62). Chlorhexidine acts on the bacterial wall in a non-specific manner, when it even at low concentrations disrupts the osmotic balance of the cell wall and the cytoplasmic membrane through the formation of non-selective pores. Cytoplasmic fluids then escape through these pores and this leads to necrosis.
The chlorhexidine molecule consists of two symmetrical 4-chlorophenyl rings and two bisguanide groups connected by a central hexamethylene bridge. It is a strongly basic molecule. At pH higher than 3.5, it has two positive charges carried on both sides of the hexamethylene bridge (Albert A., Surgeant E. R.; In: ionization constants of acids and bases. London; 1962:Methuen, P.173).
Primarily, according to the art, chlorhexidine is used in the form of salt (hydrochloride, acetate or digluconate).
Chlorhexidine has a broad-spectrum of activity against micro-organisms. This includes gram negative and gram positive bacteria, viruses (including HIV and HBV), yeasts, fungi, dermatophytes. Chlorhexidine is used in the form of gels, mucoadhesive gels, mouthwashes, sprays, chewing gums, toothpastes and other. Furthermore, it is used in dressings intended for postoperative conditions in the oral cavity (Othman S., Hauge E., Germo P.; The effect of chlorhexidine supplementation in periodontal dressing. Acta Odont Scand 1989:47:361). In addition, chlorhexidine is used in locally administered agents with controlled release of the active substance at the site of affliction (e.g. Periochip) (Killoy W. J., The use of locally delivered Chlorhexidine in the treatment of periodentitis. Clinical results. J Clin Periodontol, 1998:25:953-958).
Clinical indications of chlorhexidine are stated by, for example (Natl J Physiol Pharm Pharmacol. 2011; 1(2): 45-50; Chlorhexidine: The gold standard in chemical plaque control, http://www.scopemed.org/?mno=8252).
Chlorhexidine is widely used as an antiseptic for treatment of mucous membranes or soft tissues, both in humans and animals. For short-term use, for example in oral cavity, chlorhexidine is used as:
1) A supplement to a mechanical plaque removal when brushing teeth and during professional prophylaxis to maintain good oral hygiene;
2) After oral surgery, including periodontal surgery or the root treatment;
3) As an immediate prophylactic agent for the prevention of postextraction bacteremia;
4) An agent for recurrent mouth ulcers;
5) An agent for treatment of stomatitis caused by dentures and for treatment of dry sockets;
6) An agent during the treatment of oral infections and acute necrotizing ulcerative gingivitis
It is known that chlorhexidine can significantly reduce oral bacteria and prevent oral infection.
Chlorhexidine is used in intermittent short or medium term for:
1) Oral hygiene of physically and mentally disabled;
2) Physically compromised patients predisposed to oral infection;
3) Patients with high risk of dental caries;
4) Patients with extensive prosthetic reconstruction of abutment teeth with reduced periodontal support;
5) Patients with a dental implant.
However, the main limitation of a long-term administration of chlorhexidine, for example in preventive dentistry, is its side effect of teeth surface discolouration, back of the tongue, temporary deterioration in taste perception, reversible swelling of the parotid gland, burning and the formation of painful lesions.
However, a long-term administration of chlorhexidine is commonly used:
1) In patients with reduced tolerance to bacterial infection because of serious health problems, or as a result of a medicamentous treatment, which would include patients who have, for example agranulocytosis, leukaemia, haemophilia, thrombocytopenia, renal disease, allergy, underwent bone marrow transplantation, AIDS and another;2) In patients who are treated with cytotoxic drugs, radiotherapy or immunosuppressants;3) In patients with intermaxillary anchorage;4) In patients who are mentally unwell;5) In patients with physical disabilities or impaired motor functions;6) In geriatric patients.
The main local adverse effect of chlorhexidine in dentistry is exogenous discolouration of teeth. As early as after a few days of use of chlorhexidine, dark yellow or brown spots appear on own or false teeth. Intensity of staining is mainly related to the used concentration of the chlorhexidine and the differences in the structure of the enamel in individual patients. Other side effects include c, buds for the perception of salty taste are affected most significantly (ref 25 of the same). Sometimes burning and the formation of painful lesions of the oral mucosa are reported which appears to be an idiosyncratic reaction and is dependent on the concentration used (ref 26 of the same). Supragingival calculus may form increasingly more. Chlorhexidine on its own has a bitter taste, which is very difficult to disguise. Irritation of the oral cavity with local allergy symptoms may also occur. During the placebo-controlled clinical trials in adult patients, the following adverse effects were reported with a frequency of less than 1%: Mouth ulcers, gingivitis, trauma, ulcerations, erythema, desquamation, a coated tongue and keratinisation.
Side effects of the use of chlorhexidine digluconate in relation to mucous membranes are mentioned by, for instance (J Am Dent Assoc. 2008 February; 139(2):178-83. Adverse events associated with chlorhexidine use: results from the Department of Veterans Affairs Dental Diabetes Study. McCoy L C, Wehler C J, Rich S E, Garcia R I, Miller D R, Jones J A.)
The following side effects are associated with chlorhexidine gluconate mucous membrane:
Common side effects of chlorhexidine gluconate mucous membrane:
Tooth discoloration;
Increase of tartar formation on the teeth;
Discoloration of the mouth;
Taste problems;
Rare but serious side effects of chlorhexidine gluconate mucous membrane:
Inflammation of the salivary glands;
Inflammation of skin caused by an allergy;
Life threatening allergic reaction;
Reaction due to an allergy;
Rare side effects of chlorhexidine gluconate mucous membrane:
Reduced sensation in the mouth;
Abnormal redness of the lining of the mouth;
Inflammation of the salivary gland;
Dry mouth;
Canker sore;
Mouth irritation;
Painful, red or swollen tongue;
Sore tongue.
From the art according to published international application WO 90/10434 (filed Mar. 15, 1990) it is known, that some of these chlorhexidine deficiencies can be addressed by adding physiologically acceptable copper salt. Among other things, however, the copper compounds are physiologically acceptable to the organism with relative difficulty.
Therefore, it is clear that there is a need to partially or entirely suppress the aforementioned existing disadvantages of antiseptics, such as chlorhexidine.
The aim of the invention is that at lower concentrations, of for example chlorhexidine, in the mixture, the above negative effects are suppressed or substantially eliminated, while its antiseptic and/or disinfectant properties are maintained.